The principal objectives of the proposed work are to use linkage studies, in silico gene identification,cartilage gene expression and mutation analysis of functional and positional candidates to identify thedisease genes in osteochondrodysplasias of unknown etiology. The linkage studies will use familiescollected by outreach efforts and referral to the International Skeletal Dysplasia Registry (Core A). Thedisorders to be studied have been selected based on criteria that include their frequency, the likelihood thatidentification of the disease gene will reveal an essential component of an important biological pathway, theability to use the molecular information to improve definition of the diagnostic features and inheritancepattern(s) within a phenotypic group and the relevance to studies under the other components of theProgram Project. Through these studies, we will define new molecular mechanisms for the skeletaldysplasias and understand the normal functions of skeletal dysplasia disease genes.
The Specific Aims areto identify the loci and disease genes in three phenotypic groups: 1. Short rib polydactyly and asphxiatinq thoracic dysplasia. These two perinatal lethal disorders areamong the most frequent lethal skeletal dysplasias. They have been grouped together in the classification ofskeletal dysplasias based on shared phenotypic features and have been hypothesized to be part of aspectrum of disease that includes chondroectodermal dysplasia. We will test the hypothesis that they areeither allelic or that the disease genes are components of a pathway. 2. Recessive osteogenesis imperfecta (Ol). Knockout mice with deficiency of Crtap have a defect inprolyl hydroxylation that leads to an undermineralized skeleton resembling osteogenesis imperfecta. Thegoal of this aim is to work in collaboration with the other Projects and Cores to identify human recessive Olphenotypes with mutations in CRTAP. In cases where CRTAP is excluded, additional candidate loci will beconsidered, including a newly identified locus on chromosome 17q21-22. These interactive studies willfacilitate the definition of both the molecular basis and the clinical and histological features that characterizenovel mechanismsfor recessively inherited osteogenesis imperfecta. 3. Brachyolmia. Brachyolmia is a form of short trunk short stature with a characteristic platyspondyly andirregular margins of the vertebral bodies. The phenotype is clinically and genetically heterogeneous withdominant and recessive forms described. The goal of this aim is to use linkage studies to define the firstbrachyolmia locus and to determine the diagnostic features and natural history of the entity. Identification ofa disease gene for dominant brachyolmia will promote clarification of the diagnostic features of each formand will help define the biological basis of the phenotype
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